1. Field of the Invention
This invention relates to novel compounds which inhibit or modulate the activity of protein kinases and to pharmaceutical compositions comprising such compounds. This invention also relates to methods of treating diseases or medical conditions mediated by protein kinases using such compounds.
2. State of the Art
Protein kinases are enzymes which catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. See, for example, Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.; Stover, D. R. et al., Current Opin. in Drug Discovery, (1999) 2(4), 274-285; Adams, J. L., Current Opin. in Drug Discovery, (1999) 2(2), 96-109; and Lawrence D. S. et al., Pharmacol. Ther. (1998) 77(2), 81-114. By doing so, protein kinases mediate virtually all aspects of cell life including cell growth, cell differentiation and cell proliferation. In this regard, abnormal activity of protein kinases has been associated with a host of diseases or medical disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer). See, for example, Levitzki, A. et al., Science, (1995) 267, 1782-1788.
Accordingly, a need exists for compounds and compositions which inhibit or modulate the activity of protein kinases.
This invention provides novel compounds which inhibit or modulate the activity of protein kinases and pharmaceutical compositions comprising such compounds. Accordingly, the compounds and compositions of this invention are useful for treating diseases or medical disorders mediated by protein kinases.
The compounds of this invention are multimeric, i.e., they comprise two or more ligand(moieties covalently linked together by one or more linking groups. While not wishing to be limited by theory, it is believed that each ligand moiety of these compounds binds to a ligand binding domain of a protein kinase or a related binding site, thereby inhibiting or modulating the activity of the protein kinase. By binding to multiple binding sites, compounds of this invention exhibit improved properties including, by way of example, increased efficacy, selectivity or duration of action, relative to the monomeric ligands.
Accordingly, in one of its composition aspects, this invention provides a compound of formula I:
(L)p(X)qxe2x80x83xe2x80x83I 
and pharmaceutically acceptable salts thereof; wherein:
p is an integer of from 2 to 10;
q is an integer of from 1 to 20;
each L is a ligand independently selected from the group consisting of:
(i) a moiety of formula III: 
wherein
each Ra is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, aryl, heteroaryl and a covalent bond linking the moiety to the linker;
each Rb is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, aryl, heteroaryl and a covalent bond linking the moiety to the linker;
Rc is selected from the group consisting of aryl, alkaryl, heteroaryl and heterocycle;
provided one and only one of Ra and Rb comprises a covalent bond linking the moiety to the linker;
(ii) a moiety of formula IV: 
wherein
Rd is selected from the group consisting of aryl, alkaryl, heteroaryl and heterocycle;
Re is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and a covalent bond linking the moiety to the linker;
each Rf is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, aryl, heteroaryl and a covalent bond linking the moiety to the linker;
provided one and only one of Re or Rf comprises a covalent bond linking the moiety to the linker;
(iii) a moiety of formula V: 
wherein
each Rg is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and acyl;
Rh is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and acyl;
Ri is a covalent bond linking the moiety to the linker;
Q1 is NRixe2x80x2, O, S, alkylene or a covalent bond, where Ri, is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl or acyl;
(iv) a moiety of formula VI: 
wherein
each Rj is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and a covalent bond linking the moiety to the linker;
Rk is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, hydroxy, halogen and xe2x80x94CHO;
each Q2 is independently NRjxe2x80x2, O and S, where Rjxe2x80x2is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
provided one and only one of Rj comprises a covalent bond linking the moiety to the linker;
(v) a moiety of formula VII: 
wherein
each Rl and Rm is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
Rn is a covalent bond linking the moiety to the linker;
Q3 is NRnxe2x80x2, O, S or alkylene;
Q4 is NRnxe2x80x2, O, S, alkylene or a covalent bond, where each Rnxe2x80x2in Q3 and Q4 is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
each m is independently an integer from 1 to 3;
(vi) a moiety of formula VIII: 
wherein
each Ro is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
Rp is aryl or heteroaryl, wherein the aryl or heteroaryl group is substituted with a covalent bond linking the moiety to the linker or with xe2x80x94OZxe2x80x2 where Zxe2x80x2 is a covalent bond linking the moiety to the linker;
Z is 2H or O;
m is an integer from 1 to 3;
(vii) a moiety of formula IX: 
wherein
each Rq is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, heterocyclic and a covalent bond linking the moiety to the linker;
each Rqxe2x80x2is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and acyl;
Rs is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and acyl;
Rr is aryl or heteroaryl, wherein the aryl or heteroaryl group is substituted with a covalent bond linking the moiety to the linker;
provided one and only one of Rq or Rr comprises a covalent bond linking the moiety to the linker;
(viii) a moiety of formula X: 
wherein each Rt is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
each Ru is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy, substituted thioalkoxy and a covalent bond linking the moiety to the linker;
Q5 is NRtxe2x80x2, O, S or alkylene, where Rtxe2x80x2, is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
each m is independently an integer from 1 to 3;
provided one and only one of Ru comprises a covalent bond linking the moiety to the linker;
(ix) a moiety of formula XI: 
wherein each Rv is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
Rvxe2x80x2, is a covalent bond linking the moiety to the linker;
each Rw is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
Q6 is NRwxe2x80x2, O, S or alkylene, where Rwxe2x80x2, is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
Q6xe2x80x2 is NRvxe2x80x3, O, S or alkylene, where Rvxe2x80x2is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
each m is independently an integer from 1 to 3;
(x) a moiety of formula XII: 
wherein
each Rx is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic;
Ry is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl;
Rz is a covalent bond linking the moiety to the linker;
E is CH or N;
(xi) a moiety of formula XIII: 
wherein
each Raa is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic;
Rab is alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, thioalkoxy, substituted thioalkoxy, wherein the alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, thioalkoxy or substituted thioalkoxy group is substituted with a covalent bond linking the moiety to the linker;
D is a covalent bond, NRabxe2x80x2, O or S, where Rabxe2x80x2is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
E is CH or N;
(xii) a moiety of formula XIV: 
wherein
Rac is a covalent bond linking the moiety to the linker;
Rad is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic;
Rae is aryl or heteroaryl;
(xiii) a moiety of formula XV: 
wherein
Raf is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and acyl;
each Rag is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
Rah is aryl or heteroaryl;
Rai is aryl or heteroaryl, wherein the aryl or heteroaryl group is substituted with a covalent bond linking the moiety to the linker;
Q7 is NRafxe2x80x2, O, S or alkylene, where Rar is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
mxe2x80x2 is 1 or 2;
(xiv) a moiety of formula XVI: 
wherein
each Raj is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
Ral is aryl or heteroaryl;
each Rak is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, heterocyclic, and a covalent bond linking the moiety to the linker;
Q8 is NRalxe2x80x2, O, S or alkylene, where Ralxe2x80x2is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
m is an integer from 1 to 3;
provided one and only one of Rak comprises a covalent bond linking the moiety to the linker;
(xv) a moiety of formula XVII: 
wherein
Ram is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and a covalent bond linking the moiety to the linker;
Ran is selected from the group consisting of 4-phosphonomethylphenyl, 4-phosphonodifluoromethylphenyl, 3-carboxy-4-carboxymethoxyphenyl and 3,4-dihydroxyphenyl;
Rao is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
each Rap is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
W is N or CH;
Y is O, S, NH, N-Zxe2x80x2, CH2 or CH-Zxe2x80x2, where Zxe2x80x2 is a covalent bond linking the moiety to the linker;
m is an integer from 1 to 3;
 is an optional double bond;
provided one and only one of Ram and Y comprises a covalent bond linking the moiety to the linker;
(xvi) a moiety of formula XVIII: 
wherein
each Raq is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy, substituted thioalkoxy, a covalent bond linking the moiety to the linker and xe2x80x94NH-Zxe2x80x2, where Zxe2x80x2 is a covalent bond linking the moiety to the linker;
Rar is selected from the group consisting of 4-phosphonomethylphenyl, 4-phosphonodifluoromethylphenyl, 3-carboxy-4-carboxymethoxyphenyl and 3,4-dihydroxyphenyl;
Q9 is NRaqxe2x80x2, O, S or alkylene, where Raqxe2x80x2 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
m is an integer from 1 to 3;
provided one and only one of Raq comprises a covalent bond linking the moiety to the linker;
(xvii) a moiety of formula XIX: 
wherein
Ras is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and a covalent bond linking the moiety to the linker;
Rat is selected from the group consisting of 4-phosphonomethylphenyl, 4-phosphonodifluoromethylphenyl, 3-carboxy-4-carboxymethoxyphenyl and 3,4-dihydroxyphenyl;
Rau is aryl or heteroaryl, wherein the aryl or heteroaryl group is substituted with a covalent bond linking the moiety to the linker or with xe2x80x94OZxe2x80x2, where Zxe2x80x2 is a covalent bond linking the moiety to the linker;
Rav is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and alkaryl;
provided one and only one of Ras and Rau comprises a covalent bond linking the moiety to the linker;
(xviii) a moiety of formula XX: 
wherein
each Raw is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
each Rax is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy, substituted thioalkoxy, a covalent bond linking the moiety to the linker and xe2x80x94OZxe2x80x2, where Zxe2x80x2 is a covalent bond linking the moiety to the linker;
each m is independently an integer from 1 to 3;
provided one and only one of Rax comprises a covalent bond linking the moiety to the linker;
(xix) a moiety of formula XXI: 
wherein each Ray is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
Raz is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkaryl, acyl and a covalent bond linking the moiety to the linker;
Rba is aryl or heteroaryl;
Rbb is aryl or heteroaryl, wherein the aryl or heteroaryl group is substituted with a covalent bond linking the moiety to the linker or with xe2x80x94OZxe2x80x2, where Zxe2x80x2 is a covalent bond linking the moiety to the linker;
m is an integer from 1 to 3;
provided one and only one of Raz or Rbb comprises a covalent bond linking the moiety to the linker;
(xx) a moiety of formula XXII: 
wherein
Rbc is a covalent bond linking the moiety to the linker;
A and B are independently selected from the group consisting of 2H, O and S;
(xxi) a moiety of formula XXIII: 
wherein
each Rw is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and a covalent bond linking the moiety to the linker;
A and B are independently selected from the group consisting of 2H, O and S;
F and G are independently xe2x80x94CF2xe2x80x94or xe2x80x94CH2CH2xe2x80x94;
r is an integer from 0 to 2;
provided one and only one of Rbd comprises a covalent bond linking the moiety to the linker;
(xxii) a moiety of formula XXIV: 
wherein
Rbe is a covalent bond linking the moiety to the linker;
(xxiii) a moiety of formula XXV: 
wherein
each Rbf is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy and substituted thioalkoxy;
each Rbg is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and a covalent bond linking the moiety to the linker;
Rbh is aryl, heteroaryl or heterocyclic;
Q10 is NRbf, O, S or alkylene, where Rbf is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
m is an integer from 1 to 3;
provided one and only one of Rbg comprises a covalent bond linking the moiety to the linker;
(xxiv) a moiety of formula XXVI: 
wherein
Rbi is a covalent bond linking the moiety to the linker;
(xxv) a moiety of formula XXVII: 
wherein each Rbj is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl and a covalent bond linking the moiety to the linker;
Q11 is NRbjxe2x80x2, O, S or alkylene, where Rbjxe2x80x2, is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl or acyl;
provided one and only one of Rbj comprises a covalent bond linking the moiety to the linker;
(xxvi) a moiety of formula XXVIII: 
wherein
each Rbk is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aminoacyloxy, aryl, carboxyl, carboxyalkyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, heterocyclic, hydroxy, oxyacylamino, nitro, thioalkoxy, substituted thioalkoxy, xe2x80x94SOxe2x80x94Rbkxe2x80x2 and xe2x80x94SO2xe2x80x94Rbkxe2x80x2, where Rbkxe2x80x2is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl or heterocyclic;
Rbl is aryl or heteroaryl, wherein the aryl or heteroaryl group is substituted with a covalent bond linking the moiety to the linker or with xe2x80x94(CH2)uxe2x80x94Zxe2x80x2, where Zxe2x80x2 is a covalent bond linking the moiety to the linker and u is an integer from 1 to 3;
m is an integer from 1 to 3;
(xxvii) a moiety of formula XXIX: 
wherein
Rbn is selected from the group consisting of alkoxy, substituted alkoxy, hydroxy and xe2x80x94OZxe2x80x2, where Zxe2x80x2 is a covalent bond linking the moiety to the linker;
Rbo is aryl or heteroaryl;
Rbp is acyl, alkoxycarbonyl and a covalent bond linking the moiety to the linker;
provided one and only one of Rbn and Rbp comprises a covalent bond linking the moiety to the linker;
and further wherein each X is a linker independently selected from a group of the formula:
xe2x80x94Xaxe2x80x94Zxe2x80x94(yaxe2x80x94Z)mxe2x80x2xe2x80x94ybxe2x80x94Zxe2x80x94Xaxe2x80x94
wherein
mxe2x80x2 is an integer of from 0 to 20;
Xa at each separate occurrence is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NRxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NRxe2x80x94, xe2x80x94C(S), xe2x80x94C(S)Oxe2x80x94, xe2x80x94C(S)NRxe2x80x94or a covalent bond;
Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
Ya and Yb at each separate occurrence are selected from the group consisting of: xe2x80x94C(O)NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2C(O)xe2x80x94, xe2x80x94NRxe2x80x2C(O)NRxe2x80x2xe2x80x94, xe2x80x94C(=NRxe2x80x2)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(=NRxe2x80x2)xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94N=C(R)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94P(O)(ORxe2x80x2)xe2x80x94Oxe2x80x94, xe2x80x94S(O)nCRxe2x80x2Rxe2x80x3xe2x80x94, xe2x80x94S(O)nxe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94Sxe2x80x94Sxe2x80x94 and a covalent bond; where n is 0, 1 or 2; and
R, Rxe2x80x2 and Rxe2x80x3 at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic.
Preferably, in formula I, q is less than p. More preferably, p is 2 and q is 1.
In a preferred embodiment, each ligand in the compound of formula I is independently selected from the group consisting of:
(i) a moiety of formula A: 
(ii) a moiety of formula B: 
wherein, in formula A and B,
Rl is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and xe2x80x94(CF2)vxe2x80x94NR28R29, where v is an integer from 2 to 4;
Arl is selected from the group consisting of an aryl, alkaryl and heterocycle;
R28 is selected from group consisting of hydrogen and alkyl of 1 to 6 carbon atoms;
R29 is selected from the group consisting of 4-pyrimidinyl, 2-methylaminopyrimidin-4-yl, 2-phenoxypyrimidin-4-yl, 2-(4-methoxyphenoxy)pyrimidin-4-yl, 2-(4-fluorophenoxy)pyrimidin-4-yl, 2-(4-aminocarbonylphenoxy)pyrimidin-4-yl, 2-(4-ethylphenoxy)pyrimidin-4-yl, 2-(4-benzyloxyphenoxy)pyrimidin-4-yl, 2-(4-cyanophenoxy)pyrimidin-4-yl, 2-(4-hydroxyphenoxy)pyrimidin-4-yl, 2-(3-methoxyphenoxy)pyrimidin-4-yl, 2-(4-phenylphenoxy)pyrimidin-4-yl, 2-(4-phenoxyphenoxy)pyrimidin-4-yl, 2-(3-hydroxyphenoxy)pyrimidin-4-yl, 2-(2-hydroxyphenoxy)pyrimidin-4-yl, 2-(3,4-methylenedioxyphenoxy)pyrimidin-4-yl, 2-(3-fluorophenoxy)pyrimidin-4-yl, 2-(2-fluorophenoxy)pyrimidin-4-yl, 2-(2-methoxyphenoxy)pyrimidin-4-yl, 2-(3-trifluoromethylphenoxy)pyrimidin-4-yl, 2-(3,4-difluorophenoxy)pyrimidin-4-yl, 2-(4-methylsulfonylphenoxy)pyrimidin-4-yl, 2-(4-methoxyphenoxy)pyrimidin-4-yl, 4-pyridinyl, 2-phenoxypyridin-4-yl, 2-(4-methoxyphenoxy)pyridin-4-yl, 2-(4-fluorophenoxy)pyridin-4-yl, 2-(4-benzyloxyphenoxy)pyrimidin-4-yl, 2-(4-cyanophenoxy)pyrimidin-4-yl, 2-(4-hydroxyphenoxy)pyrimidin-4-yl, 2-(3-methoxyphenoxy)pyrimidin-4-yl, 2-(4-phenylphenoxy)pyrimidin-4-yl, 2-(4-phenoxyphenoxy)pyrimidin-4-yl, 2-(3-hydroxyphenoxy)pyrimidin-4-yl, 2-(2-hydroxyphenoxy)pyrimidin-4-yl, 2-(3,4-methylenedioxyphenoxy)pyrimidin-4-yl, 2-(3-fluorophenoxy)pyrimidin-4-yl, 2-(2-fluorophenoxy)pyrimidin-4-yl, 2-(2-methoxyphenoxy)pyrimidin-4-yl, 2-(3-trifluoromethylphenoxy)pyrimidin-4-yl, 2-(3,4-difluorophenoxy)pyrimidin-4-yl, 2-(4-methylsulfonylphenoxy)pyrimidin-4-yl, and 2-(4-methoxyphenoxy)pyrimidin-4-yl;
(iii) a moiety of formula C: 
wherein
R3 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and xe2x80x94CH2CH2OCH3;
R4 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and alkylalkoxy;
R5 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms;
(iv) a moiety of formula D: 
wherein
R6 is selected from the group consisting of substituted alkyl and xe2x80x94CHO;
R7 is selected from the group consisting of hydrogen, alkyl and acyl;
(v) a moiety of formula E: 
wherein
R8 is selected from the group consisting of hydrogen, alkoxy and halogen;
V is selected from the group consisting of amino, alkyl of 1 to 6 carbon atoms, S and O;
R9 is selected from the group consisting of hydrogen, alkoxy and halogen;
(vi) a moiety of formula F: 
wherein
R10 is selected from the group consisting of hydrogen, alkoxy, amino and substituted amino;
R11 is selected from the group consisting of hydrogen, alkoxy, halogens, amino, substituted amino and nitro;
R12 is selected from the group consisting of hydrogen, hydroxy, alkoxy and halogen;
R13 is selected from the group consisting of hydrogen, hydroxy, alkoxy and halogen;
Z is selected from the group consisting of 2H and O;
(vii) a moiety of formula H: 
wherein
R17 and R18 are independently selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms;
R19 is selected from the group consisting of alkyl of 1 to 6 carbon atoms, xe2x80x94CH2C(O)OEt, xe2x80x94(CH2)3OH, alkaryl, aryl and heteroaryl;
(viii) a moiety of formula N: 
(ix) a moiety of formula O: 
wherein
R26 is selected from the group consisting of hydrogen and acyl;
Het1 is heterocyclic or heteroaryl;
(x) a moiety of formula P: 
wherein
R27 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and substituted alkyl;
Ar3 is aryl;
(xi) a moiety of formula S: 
wherein
D is selected from the group consisting of a covalent bond, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94and xe2x80x94Oxe2x80x94;
E is selected from the group consisting of CH and N;
Ar3 is aryl;
(xii) a moiety of formula U: 
wherein
R29 is selected from the group consisting of 4-pyrimidinyl, 2-methylaminopyrimidin-4-yl, 2-phenoxypyrimidin-4-yl, 2-(4-methoxyphenoxy)pyrimidin-4-yl, 2-(4-fluorophenoxy)pyrimidin-4-yl, 2-(4-aminocarbonylphenoxy)pyrimidin-4-yl, 2-(4-ethylphenoxy)pyrimidin-4-yl, 2-(4-benzyloxyphenoxy)pyrimidin-4-yl, 2-(4-cyanophenoxy)pyrimidin-4-yl, 2-(4-hydroxyphenoxy)pyrimidin-4-yl, 2-(3-methoxyphenoxy)pyrimidin-4-yl, 2-(4-phenylphenoxy)pyrimidin-4-yl, 2-(4-phenoxyphenoxy)pyrimidin-4-yl, 2-(3-hydroxyphenoxy)pyrimidin-4-yl, 2-(2-hydroxyphenoxy)pyrimidin-4-yl, 2-(3,4-methylenedioxyphenoxy)pyrimidin-4-yl, 2-(3-fluorophenoxy)pyrimidin-4-yl, 2-(2-fluorophenoxy)pyrimidin-4-yl, 2-(2-methoxyphenoxy)pyrimidin-4-yl, 2-(3-trifluoromethylphenoxy)pyrimidin-4-yl, 2-(3,4-difluorophenoxy)pyrimidin-4-yl, 2-(4-methylsulfonylphenoxy)pyrimidin-4-yl, 2-(4-methoxyphenoxy)pyrimidin-4-yl, 4-pyridinyl, 2-phenoxypyridin-4-yl, 2-(4-methoxyphenoxy)pyridin-4-yl, 2-(4-fluorophenoxy)pyrimidin-4-yl, 2-(4-benzyloxyphenoxy)pyrimidin-4-yl, 2-(4-cyanophenoxy)pyrimidin-4-yl, 2-(4-hydroxyphenoxy)pyrimidin-4-yl, 2-(3-methoxyphenoxy)pyrimidin-4-yl, 2-(4-phenylphenoxy)pyrimidin-4-yl, 2-(4-phenoxyphenoxy)pyrimidin-4-yl, 2-(3-hydroxyphenoxy)pyrimidin-4-yl, 2-(2-hydroxyphenoxy)pyrimidin-4-yl, 2-(3,4-methylenedioxyphenoxy)pyrimidin-4-yl, 2-(3-fluorophenoxy)pyrimidin-4-yl, 2-(2-fluorophenoxy)pyrimidin-4-yl, 2-(2-methoxyphenoxy)pyrimidin-4-yl, 2-(3-trifluoromethylphenoxy)pyrimidin-4-yl, 2-(3,4-difluorophenoxy)pyrimidin-4-yl, 2-(4-methylsulfonylphenoxy)pyrimidin-4-yl, and 2-(4-methoxyphenoxy)pyrimidin-4-yl;
(xiii) a moiety of formula V: 
wherein
R30 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, halogen and alkoxy;
R31 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, halogen, alkoxy and Zv;
R32 is selected from the group consisting of hydrogen, amino, substituted amino, alkoxy, xe2x80x94NHCOCH3, and Zv, provided one and only one of R3, and R32 is Zv; and
(xiv) a moiety of formula Z: 
wherein
R34 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, halogen and substituted alkyl;
R35 is selected from the group consisting of hydrogen and halogen;
R36, R37, and R38 are selected from the group consisting of hydrogen, xe2x80x94NO2, alkyl, substituted alkyl, amino, substituted amino, alkoxy, hydroxy and halogen;
and further wherein Za, Zb), Zc, Zd, Ze, Zf, Zh, Zn, Zo, Zp, Zs, Zu, Zv, and Zz, are covalent bonds linking the moiety to the linker;
and stereoisomers and analogs thereof.
In another preferred embodiment, the ligands employed are ligands for the SH2 or SH3 sites of protein kinases. In this embodiment, each ligand in the compound of formula I is independently selected from the group consisting of:
(i) a moiety of formula I: 
(ii) a moiety of formula J: 
wherein, in formula I and J,
W is selected from the group consisting of N and CH;
Y is selected from the group consisting of O, S and NH;
R20 is selected from the group consisting of. 
R21 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy, amino and substituted amino;
is an optional double bond;
(iii) a moiety of formula K: 
wherein
R20 is selected from the group consisting of: 
(iv) a moiety of formula L: 
(v) a moiety of formula M: 
wherein, in formula L and M,
R22 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and substituted alkyl;
R23 is 
R24 is selected from the group consisting of hydrogen and acyl;
R25 is selected from the group consisting of alkyl and cycloalkyl;
R39 is selected from the group consisting of 
Ar2 is selected from the group consisting of alkyl of 1 to 6 carbon atoms, substituted alkyl and aryl;
and further wherein Zi, Zj, Zk, Zl, and Zm are covalent bonds linking the moiety to the linker;
and stereoisomers and analogs thereof.
In still another preferred embodiment, the ligands employed are ligands for Src and Zap families of protein kinases. In this embodiment, each ligand in the compound of formula I is a moiety of formula Q: 
wherein
Zq is a covalent bond linking the moiety to the linker;
and stereoisomers and analogs thereof.
In yet another preferred embodiment, the ligands employed are other ligands for the Src family of protein kinases. In this embodiment, each ligand in the compound of formula I is a moiety of formula G: 
wherein
R14 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and alkaryl;
R15 is selected from the group consisting of hydrogen, alkoxy and halogen;
R16 is selected from the group consisting of hydrogen, alkoxy, hydroxy and halogen;
and further wherein Zg is a covalent bond linking the moiety to the linker;
and stereoisomers and analogs thereof.
In another preferred embodiment, the ligands employed are ligands for the PKC family of protein kinases. In this embodiment, each ligand in the compound of formula I is independently selected from the group consisting of: 
wherein
A and B are independently selected from the group consisting of 2H, S and O;
(ii) a moiety of formula T: 
wherein
F is selected from the group consisting of xe2x80x94CH2xe2x80x94and xe2x80x94CH2CH2xe2x80x94;
G is selected from the group consisting of xe2x80x94CH2xe2x80x94and xe2x80x94CH2CH2xe2x80x94;
R28 is selected from the group consisting of hydrogen and alkyl of 1 to 6 carbon atoms;
r is 0, 1, or 2; and
(iii) a moiety of formula AA: 
and further wherein Zf, Zt and Zaa, are covalent bonds linking the moiety to the linker;
and stereoisomers and analogs thereof.
In still another preferred embodiment, the ligands employed are ligands for the MAP family of protein kinases. In this embodiment, each ligand in the compound of formula I is independently selected from the group consisting of:
(i) a moiety of formula W: 
wherein
R33 is selected from the group consisting of aryl and heterocyclic;
(ii) a moiety of formula X: 
(iii) a moiety of formula Y: 
and further wherein Zw, ZX and Zy are covalent bonds linking the moiety to the linker; and stereoisomers and analogs thereof.
In yet another preferred embodiment, the ligands employed are ligands for receptor tyrosine kinases. In this embodiment, each ligand of the compounds of formula I is independently selected from the group consisting of:
(i) a moiety of formula AB: 
(ii) a moiety of formula AC: 
(iii) a moiety of formula AD: 
(iv) a moiety of formula AE: 
(v) a moiety of formula AF: 
(vi) a moiety of formula AG: 
(vii) a moiety of formula AH: 
(viii) a moiety of formula Al: 
(vix) a moiety of formula AJ: 
wherein
R41 is independently selected from the group consisting of hydrogen, 4xe2x80x94CH3, 5xe2x80x94CH3 and 4,5xe2x80x94dixe2x80x94CH3;
R42 is independently selected from the group consisting of hydrogen, CF13, xe2x80x94F, xe2x80x94Cl and xe2x80x94NO2;
R43 is independently selected from the group consisting of xe2x80x94Zac, hydrogen, xe2x80x94(CH2),xe2x80x94NR45Zac and xe2x80x94(CH2)vxe2x80x94NR45R46;
R44 is independently selected from the group consisting of xe2x80x94Zad, hydrogen, xe2x80x94CH3, xe2x80x94CH2CH3 and t-butyl;
R55 is independently selected from the group consisting of hydrogen, xe2x80x94CH3, xe2x80x94CH2CH3 and xe2x80x94CH2CH2NMe;
R46 is independently selected from the group consisting of hydrogen, xe2x80x94CH3 and ethyl;
R47 is independently selected from the group consisting of hydrogen, 2xe2x80x94CH13, 3xe2x80x94CH3, 5xe2x80x94CH3, 5xe2x80x94Cl, 5xe2x80x94OCH3 and 5xe2x80x94N(CH3)2;
R48 is independently selected from the group consisting of p-C6H4xe2x80x94CH2P(O)(OH)2, p-OCH2COOH-m-COOHxe2x80x94C6H3 p-C6H4xe2x80x94OP(O)(OH)2 and p-C6H4xe2x80x94CF2P(O)(OH)2;
R49 is independently selected from the group consisting of acetyl, t-BOC, xe2x80x94Cbz, and xe2x80x94C(O)Ph;
R50 is independently selected from the group consisting of C1-5 alkyl (preferably methyl, ethyl and propyl);
Ar4 is independently selected from the group consisting of 4-Cl-3-F-C6H3, 3-Brxe2x80x94C6H4, 3-Clxe2x80x94C6H4, 3-Fxe2x80x94C6H4, 4-Brxe2x80x94C6H4, 4-Clxe2x80x94C6H4, and 3,4-dihalophenyl;
Ar5 is independently selected from the group consisting of C6H5, p-C6H4OH, and other substituted phenyl groups;
u is an integer from 1 to 3,
v is an integer from 2 to 4,
W is N or CHF,
Y is CH or N;
and further wherein Zab, Zac, Zad, Zac, Zaf, Zag, Zah, Zai and Zaj are covalent bonds linking the moiety to the linker;
and stereoisomers and analogs thereof.
In another preferred embodiment, the above ligands further comprise a moiety of formula ABxe2x80x2: 
wherein R41, R42, u and Zab are as defined herein.
In another preferred embodiment, each ligand in the compound of formula I is independently selected from the group consisting of a moiety of formula A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, X, Y, Z, AA, AB, ABxe2x80x2, AC, AD, AE, AF, AG, AH, AI and AJ as defined herein.
Suitable analogs include alkylated, acylated, animated, thiolated, hydroxylated, amidated, carboxylated, phosphorylated, sulfonated and halogenated analogs thereof.
In another of its composition aspects, this invention provides a compound of formula II:
L-X-Lxe2x80x83xe2x80x83II 
wherein L and X are as defined herein; and pharmaceutically-acceptable salts thereof.
In yet another of its composition aspects, this invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a thereapeutically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof.
The compounds of this invention are effective inhibitors or mediators of protein kinase activity and as such, they are useful for treating diseases or medical disorders mediated by protein kinases. Accordingly, in one of its method aspects, this invention provides a method of treating a disease or medical disorder mediated by a protein kinase, the method comprising administering to a mammal a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a thereaputically effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof. Representative diseases or medical disorders mediated by protein kinases include, by way of illustration, hyperproliferative disorders such as cancer, psoriasis, hepatic cirrhosis, diabetes, atherosclerosis, angiogenesis, restenosis, ocular diseases, rheumatoid arthritis and other inflammatory disorders, autoimmune disease and a variety of renal disorders.
This invention also provides a compound of formula I or II for use in medical therapy or for use in the manufacture of a formulation or medicament for treating a disease or medical condition mediated by a protein kinase.